Diazepine derivatives in the treatment of tension, agitation and epilepsy

ABSTRACT

Compounds of the class of 6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carboxamides, their 5-oxides and their pharmaceutically acceptable acid addition salts have valuable pharmacological properties and are active ingredients for therapeutic compositions. In particular, these new compounds have an anti-convulsive and anti-aggressive action and potentiate the action of anaesthetics. Specific embodiments are N,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, N,N-dimethyl-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide and 6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide.

This is a division, of application Ser. No. 418,137, filed Nov. 21, 1973now U.S. Pat. No. 3,948,931

DETAILED DESCRIPTION

The present invention relates to new diazepine derivatives, totherapeutical preparations containing the new compounds, and to the usethereof.

The diazepine derivatives according to the invention correspond to thegeneral formula I ##STR1## wherein R₁ represents hydrogen or an alkylgroup having 1 to 3 carbon atoms, and

R₂ and R₃ represent hydrogen, alkyl groups having 1 to 6 carbon atoms,or hydroxyalkyl groups having 2 to 6 carbon atoms, or aralkyl groupshaving 7 to 9 carbon atoms, whereby, when R₂ and R₃ simultaneouslyrepresent alkyl groups as aforesaid, these alkyl groups may be boundtogether in the β-oder γ-position either direct or via an oxygen atom,the imino group, or a lower alkylimino or hydroxyalkylimino group havingat most 4 carbon atoms to form a bivalent radical having in all at most10 carbon atoms, and the rings A and B are unsubstituted or substitutedby halogen up to

Atomic number 35, alkyl or alkoxy groups each having 1 to 6 carbonatoms, or by trifluoromethyl or nitro groups.

The invention relates also to the 5-oxides of compounds of the generalformula I, and to the addition salts of compounds of the general formulaI with inorganic and organic acids.

As an alkyl group in the compounds of the general formula I, R₁ is, forexample, the methyl, ethyl or propyl group; as alkyl groups having 1 to6 carbon atoms, R₂ and R₃ are, for example, propyl, isopropyl, butyl,isobutyl, pentyl, isopentyl or hexyl groups, and preferably methyl orethyl groups; as hydroxyalkyl groups having at most 6 carbon atoms, theyare, for example, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl,3-hydroxybutyl, 2-hydroxy-1-methyl-propyl, 2-hydroxypentyl,2-hydroxyhexyl and, in particular, 2-hydroxyethyl groups; and as aralkylgroups having at most 7 to 9 carbon atoms, they are, for example,benzyl, phenethyl, α-, o-, m- or p-methylbenzyl, 3-phenylpropyl orα-methylphenethyl groups.

Alkyl groups R₂ and R₃ bound together in the β- or γ-position in theabove defined manner form, together with the adjacent nitrogen atom,i.e. as a grouping NR₂ R₃, e.g. the 1-pyrrolidinyl, piperidino,hexahydro-1H-azepin-1-yl, morpholino, 1-piperazinyl orhexahydro-1H1,4-diazepin-1-yl group. The two last-mentioned groups canbe substituted in the 4-position, i.e. in the imino group, e.g. bymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl or 3-hydroxybutyl group, while all theaforementioned rings can, in addition, be substituted on carbon atoms byethyl, propyl or, in particular, methyl groups. The following may begiven as examples of C-alkyl-substituted and C- and N-substitutedradicals NR₂ R₃ : the 2,5-dimethyl-1-pyrrolidinyl, 2-methyl-, 3-methyl-and 4-methyl-piperidino, 2,6-dimethylpiperidino,2,4,6-trimethyl-piperidino, 2,2,6,6-tetramethylpiperidino,2,5-dimethyl-1-piperazinyl, 2,4,5-trimethyl-1-piperazinyl,2,4,6-trimethyl-1-piperazinyl and 3,4,5-trimethyl-1-piperazinyl groups.

Halogen atoms as substituents of rings A and B are fluorine, chlorine orbromine atoms; while alkyl groups and alkoxy groups having 1 to 6 carbonatoms are respectively, e.g. methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert.butyl, pentyl, isopentyl, 2,2-dimethylpropyl, hexyl orisohexyl groups and methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentyloxy, isopentyloxy, 2,2-dimethyl-propoxy, hexyloxy orisohexyloxy groups. A substituent of ring A is, in particular, in the8-position and is preferably fluorine, bromine, the nitro group, thetrifluoromethyl group and, in particular, chlorine. Ring B is preferablyunsubstituted, or substituted in any position by fluorine, chlorine orbromine, the trifluoromethyl group or the nitro group, especially,however, by fluorine or chlorine in the o-position.

The compounds of the general formula I, their 5-oxides and thecorresponding addition salts with inorganic and organic acids possessvaluable pharmacological properties. They have a central depressantaction, particularly an anticonvulsive and anti-aggressive action, andpotentiate the action of anaesthetics. Their anticonvulsive activity canbe demonstrated, for example, in the pentetrazole test on the mouse withoral doses of from ca. 0.5 mg/kg. The central depressant, particularlyanticonvulsive, properties, as well as further properties, which can beverified by selected standard tests [cp. W. Theobald and H. A. Kunz,Arzneimittelforsch. 13, 122 (1963) and also W. Theobald et al.,Arzneimittelforsch. 17, 561 (1967)], characterise the compounds of thegeneral formula I and their 5-oxides, as well as their pharmaceuticallyacceptable addition salts with inorganic and organic acids, as activesubstances for tranquillisers and anticonvulsants, which can be used,for example, for the treatment of states of tension and agitation, aswell as for the treatment of epilepsy.

Of particular importance are compounds of the general formula I in whichR₁ is hydrogen, R₂ and R₃ each independently represent hydrogen or alkylgroups having 1 to 6 carbon atoms, preferably methyl or ethyl groups,ring A is unsubstituted or preferably substituted by a halogen atom upto atomic number 35, the nitro or trifluoromethyl group, and ring B iseither unsubstituted, or substituted by one of the substituentsmentioned for ring A. Particularly valuable compounds within this groupof compounds are, on the one hand, those having one of theabove-mentioned substituents, especially a chlorine atom, in ring A inthe 8-position and, on the other hand, compounds with an unsubstitutedring B or a ring B substituted in the ortho-position by fluorine orchlorine, and, in particular, those compounds which contain hydrogen asR₁ and hydrogen, methyl or ethyl groups as R₂ and R₃ and combine thedefined substitution characteristics for rings A and B, such asN-methyl-, N-ethyl- andN,N-diethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4] benzodiazepine-1-carboxamide and, in particular,6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamideandN,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide,and the corresponding compounds having the 6-(o-fluorophenyl)- or6-(o-chlorophenyl)group in place of the phenyl group;, such as6-(o-fluorophenyl)8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide,N,N-dimethyl-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, N-methyl-, N-ethyl- andN,N-diethyl-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamideand, in particular,6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamideandN,N-dimethyl-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide.

The compounds of the general formula I, their 5-oxides and their acidaddition salts are prepared according to the invention by a process inwhich an aldehyde of the general formula II ##STR2## wherein R₁ has themeaning given under formula I, and rings A and B can be substituted asdefined under formula I, is reacted with a compound of the generalformula III ##STR3## wherein R₂ and R₃ have the meanings given underformula I, in the presence of an alkali metal cyanide and of a selectiveoxidising agent; and, optionally, the resulting reaction productoxidised to a 5-oxide; or, optionally, converted into an addition saltwith an inorganic or organic acid. The alkali metal cyanide employed is,for example, potassium cyanide and especially sodium cyanide. Byselective oxidising agents are meant such ones which, under the reactionconditions, do not act on the aldehyde group of the starting material offormula II, but which are able to oxidise the hydroxymethylene group ofthe intermediately formed cyanohydrin to the carbonyl group. Aparticularly suitable oxidising agent is manganese dioxide. Preferably,the reactions with manganese dioxide are performed in isopropanol in thecold state, e.g. between -10° C and +10° C, preferably at 0° C, or inanother lower secondary alkanol, to which can be added a further organicsolvent inert under the reaction conditions, preferably one having agood dissolving capacity for the starting materials of the generalformula II, such as, for example, dioxane. Relative to the compound ofthe general formula II, there are used, for example, an appreciableexcess of the compound of the general formula III, the ca. 5-fold molaramount of alkali metal cyanide and the ca. 20-fold molar amount ofmanganese dioxide, with a reaction time of 2 to 6 hours, preferably ca.4 hours.

According to a second process, the compounds of the general formula I,their 5-oxides and their acid addition salts are prepared by thereaction of a reactve functional derivative of a carboxylic acid of thegeneral formula IV ##STR4## wherein R₁ has the meaning given underformula I and rings A and B can be substituted as defined under formulaI, or of the 5-oxide of such a compound, with a compound of thepreviously defined general formula III in which R₂ and R₃ have themeanings given under formula I; and, optionally, the oxidation of aresulting compound of the general formula I to its 5-oxide; or theconversion thereof into an addition salt with an inorganic or organicacid. Suitable reactive functional derivatives of carboxylic acids ofthe general formula IV are, for example, lower alkyl esters, such as themethyl esters or ethyl esters of carboxylic acids of the general formulaIV, which can be reacted at room temperature, or if necessary withheating, in the presence or absence of an inert organic solvent, suchas, e.g. dioxane or tetrahydrofuran, with compounds of the generalformula III to give the corresponding amides of the general formula I.

The preparation of reactive functional derivatives of carboxylic acidsof the general formula IV is described further on in the text. Compoundsof the general formula III are known in considerable numbers, and otherscan be obtained in a manner analogous to that in the case of the knowncompounds.

A third process for the preparation of the new compounds of the generalformula I, their 5-oxides and their acid addition salts is one in whicha compound of the general formula V ##STR5## wherein X represents themercapto group, a lower alkoxy or alkylthio group which are optionallyactivated by a substituent, or an optionally mono- or disubstitutedamino group,

R₁ has the meaning given under formula I, and rings A and B can besubstituted as defined under formula I, is condensed with a compound ofthe general formula VI ##STR6## wherein R₂ and R₃ have the meaningsgiven under formula I; and, optionally, the reaction product obtainedoxidised to its 5-oxide, or converted into an addition salt with aninorganic or organic acid.

As a lower alkylthio or alkoxy group, X is preferably the methylthio orethylthio group or the methoxy or ethoxy group. These groups can beactivated by a substituent. Such activated groups are, e.g. the o- orp-nitro-benzylthio group or the o- or p-nitrobenzyloxy group. As amonosubstituted amino group, X is, in particular, a lower alkylaminogroup such as the methylamino group, or an aralkylamino group such asthe benzylamino group. As a disubstituted amino group, X is, inparticular, a lower dialkylamino group, such as the dimethylamino group.

The reaction according to the invention is preferably performed at areaction temperature of ca. 80° to 160° C in an inert solvent. Suitableinert solvents are, for example, hydrocarbons such as toluene or xylene,halogenated hydrocarbons such as chlorobenzene, a lower alkanol such as,e.g. ethanol, isopropanol or butanol, ethereal liquids such asdiethylene glycol dimethyl ether, diethylene glycol diethyl ether ordioxane and amides, especially N,N,N',N',N",N"-hexamethyl-phosphoricacid triamide, or sulphoxides such as dimethylsulphoxide. The reactiontimes are between ca. 1 and 24 hours.

Starting substances embraced by the general formula V are described inthe literature; see, among other references, L. H. Sternbach and E.Reeder, J.Org.Chem. 26, 1111 (1961), S. C. Bell et al., J.Med.Chem. 5,63 (1962), G. A. Archer and L. H. Sternbach, J.Org.Chem. 29, 231 (1964)and J. Farber et al., J.Med.Chem. 7. 235 (1964). Also compounds embracedby the general formula VI are described, such as 5-methyl-semioxamazide(N-methyloxamic acid-hydrazide) by G. Tirie in Rec.trav.chim. 52, 363(1933), 5-ethylsemioxamazide [Zh.Obshch.Khim. 34 (1), 28-32 (1964), CA60, 10391 d]and 5-allyl-semioxamazide [U.S.-Pat. No. 2,835,703, CA 52, P15568 f]. Further compounds of the general formulae V and VI can beprepared in a manner analogous to that for the known compounds. Forexample, further starting materials of the general formula V having anoptionally substituted amino group X are obtained by reduction of thecorresponding 4-oxides described in the literature, and furthercompounds of the general formula VI, e.g. by reaction of oxamic acidmethyl esters or oxamic acid ethyl esters, N-substituted according tothe definition for R₂ and R₃, with hydrazine.

Compounds of the general formula I wherein R₂ and R₃ denote hydrogenatoms, while R₁ has the meaning given under formula I and rings A and Bcan be substituted as defined under formula I, their 5-oxides and theiracid addition salts are prepared by a fourth process in which a nitrileof the general formula VII ##STR7## wherein R₁ has the meaning givenunder formula I, and rings A and B can be substituted as defined underformula I, or the 5-oxide thereof, is partially hydrolysed; and,optionally, a resulting compound of the general formula I oxidised toits 5-oxide; or converted into an addition salt with an inorganic ororganic acid. The partial hydrolysis can be performed in an alkaline,aqueous-organic medium or in an acid aqueous or aqueous-organic mediumunder mild conditions, i.e., for example, at a temperature of between 0°C and room temperature or, if necessary, at slightly elevatedtemperature. As an alkaline medium, it is possible to use, for example,a diluted, e.g. 0.2N to 2N, alkali hydroxide solution, particularlysodium or potassium hydroxide solution, together with an organic solventmiscible with water or readily soluble in water, such as, e.g. methanol,ethanol or dioxane. The acid medium employed can be, for example, dilutesulphuric acid or hydrochloric acid in the presence or absence oforganic solvents, such as, e.g. acetic acid or dioxane. The preparationof the nitriles of the general formula VII is described later on in thetext.

The oxidation reaction to give the corresponding 5-oxides, whichoptionally follows the processes according to the invention for thepreparation of compounds of the general formula I, is preferablyperformed by means of hydrogen peroxide or peroxy acids at a temperatureof ca. 0° to 70° C. Suitable peroxy acids are, e.g. peroxyacetic acid orperoxybenzoic acids, such as peroxybenzoic acid or, in particular,m-chloroperoxybenzoic acid. The oxidising agents are preferably used ina solvent, e.g. peroxyacetic acid in acetic acid and peroxybenzoic acidsin halogenated hydrocarbons, such as methylene chloride or chloroform.

The starting materials of the general formula II for the first-mentionedprocess for the preparation of the compounds of the general formula Ican be obtained, for example, by condensation of compounds of thegeneral formula V, of which, as already mentioned, some representativesare known, with benzoyloxyacetic acid hydrazide to corresponding1-(benzyloxymethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines; splittingof these with hydrobromic acid in acetic acid to the corresponding4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-methanols; and oxidationthereof by means of manganese dioxide, e.g. in benzene, or by means ofdimethylsulphoxide in the presence of dicyclohexylcarbodiimide andphosphoric acid.

As starting materials for the second-mentioned process for thepreparation of compounds of the general formula I, the lower alkylesters of carboxylic acids of the general formula IV are obtainable, forexample, by reaction of an aldehyde of the general formula II with alower alkanol, in the presence of sodium cyanide and manganese dioxidein acetic acid at room temperature.

The nitriles of the general formula VII, required as starting materialsfor the fourth-mentioned process, are obtained, for example, byoxidation of aldehydes of the general formula II in the presence ofammonia, with use of oxidising agents stronger than those required forthe first-mentioned process for the preparation of compounds of thegeneral formula I. Preferably, oxidation is performed with leadtetraacetate in an inert organic solvent, such as, e.g. benzene, attemperatures of between ca. 0° and 50° C, preferably at roomtemperature.

A further process for the preparation of nitriles of the general formulaVII comprises the oxidation of corresponding compounds containing,instead of the cyano group, the aminomethyl group. Oxidation in thiscase too is preferably performed by means of lead tetraacetate. Finally,reference is also made to the possibility of obtaining the nitriles ofthe general formula VII, widely applicable as intermediates, bydehydration of the corresponding amides embraced by the general formulaI in which R₂ and R₃ denote hydrogen atoms, for example, by means ofphosphorus oxychloride or phosphorus pentoxide in an organic solventsuch as, e.g. dimethylformamide.

The present invention relates also to such modifications of theaforementioned processes, whereby a process is interrupted at somestage, or whereby a compound occurring as an intermediate at some stageis taken as the starting product and the uncompleted steps areperformed, or whereby a starting material is formed under the reactionconditions, or, optionally, is used in the form of a salt. Instead ofracemates of optically active compounds, it is also possible to use asstarting materials isolated optical antipodes or, in the case ofdiastereomeric compounds, a specific racemate. Furthermore, suchstarting materials can be optionally used in the form of salts.

The compounds of the general formula I which are obtained by theprocesses according to the invention are optionally converted in theusual manner into their addition salts with inorganic and organic acids.Acids used for salt formation are, for example, hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, perchloric acid,methanesulphonic acid, ethanesulphonic acid or citric acid, preferablyin the presence of a solvent, such as, e.g. acetone, methanol, ethanolor ether, or mixtures thereof.

The compounds of the general formula I, as well as their 5-oxides andthe corresponding, pharmaceutically acceptable acid addition salts, arepreferably administered orally or rectally. The daily doses vary between0.02 and 2 mg/kg for warm-blooded animals. Suitable dosage units such asdragees, tablets or suppositories, preferably contain 0.5 - 50 mg of anactive substance according to the invention, i.e. of a compound of thegeneral formula I, of its 5-oxide or of a pharmaceutically acceptableacid addition salt of the former. The said dosage units are prepared bycombination of the active substance with solid pulverulent carriers,such as lactose, saccharose, sorbitol or mannitol; starches such aspotato starch, maize starch or amylopectin, also laminaria powder orcitrus pulp powder; cellulose derivatives or gelatine, optionally withthe addition of lubricants such as magnesium or calcium stearate orpolyethylene glycols, to form tablets or dragee cores. Thelast-mentioned are coated, for example, with concentrated sugarsolutions which may also contain, e.g gum arabic, talcum and/or titaniumdioxide, or with a lacquer dissolved in readily volatile organicsolvents or solvent mixtures. Dyestuffs can be added to these coatings,e.g. for indentification of the various dosage amounts. Further suitableoral dosage units are hard gelatine capsules, as well as soft closedcapsules made from gelatine and a softener such as glycerin. The formercontain the active substance preferably as a granulate in admixture withlubricants such as talcum or magnesium stearate, and optionallystabilisers such as sodium metabisulphite or ascorbic acid.

The following examples further illustrate the preparation of tablets,dragees and suppositories:

a. 50.0 g ofN,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamideis mixed with 500 g of lactose and 292 g of potato starch; the mixtureis moistened with an alcoholic solution of 8 g of gelatine, andgranulated through a sieve. After drying of the granulate, 60 g ofpotato starch, 60 g of talcum, 10 g of magnesium stearate and 20 g ofhighly dispersed silicon dioxide are mixed in, and the mixture issubsequently pressed out to form 10,000 tablets each weighing 105 mg andeach containing 5 mg of active substance; the tablets can optionally beprovided with grooves to give a more precise adjustment of the dosageamount.

b. 2.5 g of N,N-dimethyl-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide is well mixed with 16 g ofmaize starch and 6 g of highly dispersed silicon dioxide. The mixture ismoistened with a solution of 2 g of stearic acid, 6 g of ethylcelluloseand 6 g of stearin in ca. 70 ml of isopropyl alcohol, and granulatedthrough a sieve III (Ph.Helv. V). The granulate is dried for ca. 14hours and subsequently passed through sieve III-IIIa. It is then mixedwith 16 g of maize starch, 16 g of talcum and 2 g of magnesium stearate,and the mixture pressed out to form 1000 dragee cores. These are coatedwith a concentrated syrup of 2 g of lacca, 7.5 g of gum arabic, 0.15 gof colouring agent, 2 g of highly dispersed silicon dioxide, 25 g oftalcum and 53.35 g of sugar, and subsequently dried. The drageesobtained each weigh 161.0 mg and each contain 1.0 mg of activesubstance.

c. 10 g of N,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide and 1990 g of finely groundsuppository foundation substance (e.g cocoa butter) are thoroughly mixedand then melted. From the melt, maintained homogeneous by stirring, arepoured 1000 suppositories each weighing 2 g and each containing 10 mg ofactive substance.

The following examples further illustrate the preparation of the newcompounds of the general formula I as well as of starting materials nothitherto known; the examples are, however, in no way intended to limitthe scope of the invention. The temperature values are expressed indegrees Centigrade.

EXAMPLE 1

0.245 g (0.005 mole) of sodium cyanide is added at 0°, with stirring, tothe saturated solution of ammonia in 15 ml of isopropanol. After 5minutes, a solution of 0.322 g (0.001 mole) of6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehydein ca. 10 ml of isopropanol is added together with 0.87 g of manganesedioxide. After a further 10 minutes, another addition is made of 0.87 g(total 0.02 mole) of manganese dioxide, and the mixture stirred for 4hours at 0°. After the addition of ca. 40 ml of methylene chloride, thereaction mixture is filtered and the filtrate concentrated byevaporation. Crystallisation of the residue from methanol/ethylacetate/petroleum ether yields6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide,M.P. 285°-289°.

The starting material is prepared as follows:

a. A mixture of 1.3 g of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-methanol [cp., e.g. German`Offenlegungsschrift` No. 2,156,472, Belgian Pat. No. 775,558] , 3.4 gof manganese dioxide and 80 ml of benzene is refluxed for 2 hours. Thereaction mixture is then filtered through a layer of silica gel, and thefiltrate concentrated by evaporation. The residue is chromatographedthrough silica gel (Merck, 0.063 - 0.2 mm particle size) with variousethyl acetate/ethanol mixtures of increasing ethanol content as theeluant. The fractions eluted with ethyl acetate/ethanol (4:1) arecombined and concentrated by evaporation. The residue is crystallisedfrom ethyl acetate/petroleum ether to obtain6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde, M.P. 161°-163°.

EXAMPLE 2

80 ml of isopropanol is added to 120 ml of a 20% solution ofdimethylamine in dioxane. After this has cooled to 0°, additions aremade, with stirring, of 3.7 g (0.075 mole) of sodium cyanide and, after5 minutes, of a solution of 4.8 g (0.015 mole) of6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde[see Example 1 a)] in 50 ml of dioxane/isopropanol (1:1), as well as of13 g of manganese dioxide. After 10 minutes, a further addition is madeof 13 g of manganese dioxide (total 0.3 mole), and the mixturesubsequently stirred for 4 hours at 0°. After the addition of methylenechloride, the reaction mixture is filtered and the filtrate concentratedby evaporation. Crystallisation of the residue from ethylacetate/petroleum ether yieldsN,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide,M.P. 180°- 181° C.

EXAMPLE 3

3 ml of a 20% solution of dimethylamine in dioxane is added at 25° to asolution of 0.705 g (0.002 mole) of6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxylicacid methyl ester in 10 ml of methanol. After 24 hours, the reactionmixture is concentrated by evaporation, and the residue crystallisedfrom ethyl acetate/petroleum ether to obtainN,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a]1,4]benzodiazepine-1-carboxamide, M.P. 180°-181°.

The starting material is prepared as follows:

A mixture of 1.62 g (0.005 mole) of6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde[cp. Example 1 a)], 20 ml of methanol, 1.225 g (0.025 mole) of sodiumcyanide, 8.70 g (0.10 mole) of manganese dioxide and 0.40 g of glacialacetic acid is stirred for 16 hours at 25°. The reaction mixture isdiluted with methanol, filtered through a layer of kieselguhr and thefiltrate concentrated by evaporation. The residue is dissolved inmethylene chloride, this solution washed with water and saturated sodiumchloride solution, dried over magnesium sulphate and concentrated byevaporation. The oily residue is chromatographed on silica gel (Merck,0.063 - 0.2 mm particle size) with ethyl acetate/methanol (9:1) aseluant. The fractions containing the desired product [R_(f) = 0.7 in theeluant system ethyl acetate/isopropanol (7:1)] are combined,concentrated by evaporation, and the residue crystallised from ethylacetate to obtain 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxylic acid methyl ester, M.P. 216°-217°.

EXAMPLE 4

A solution of 1.60 g (0.005 mole) of6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carbonitrilein a mixture of 50 ml of methanol and 50 ml of 1N sodium hydroxidesolution is allowed to stand for ca. 10 minutes at 25°. The reactionmixture is then neutralised with 2N hydrochloric acid, and concentratedto about half its volume. The concentrate is extracted in methylenechloride, the organic solution washed with saturated sodium chloridesolution, dried over sodium sulphate and concentrated by evaporation.The residue is crystallised from methanol/ethyl acetate/petroleum etherto obtain 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 285°-289°.

The nitrile required as starting material is prepared as follows:

a. A solution of 4.8 g (0.015 mole) of6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde[see Example 1 a)] in abs. benzene is saturated with ammonia. Aftercooling of the solution to 0°, an addition is made portionwise, with alight flow of ammonia gas and in the course of 45 minutes, of 14.0 g(0.030 mole) of lead tetraactetate. The reaction mixture is then stirredfor a further 24 hours at 25°; it is subsequently diluted with ether andfiltered through kieselguhr. The filtrate is washed with 1N hydrochloricacid, water and saturated sodium chloride solution, dried over magnesiumsulphate and concentrated by evaporation. The residue is chromatographedthrough silica gel with the use of ethyl acetate as eluant. Thefractions containing the desired nitrile [R_(f) = 0.63 in the eluantsystem ethyl acetate/isopropanol (7:1)] are combined, and concentratedby evaporation. The residue is crystallised from ethyl acetate/petroleumether to obtain 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.

The nitrile can also be prepared in the following manner:

b. 4 ml of phosphorus oxychloride is added to a solution of 1.69 g(0.005 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a ][1,4]benzodiazepine-1-carboxamide in 5ml of dimethylformamide, andstirring maintained for 10 minutes at 80°. The reaction mixture is thenpoured on ice and extracted with ethylene chloride. The extract iswashed with water and saturated sodium chloride solution, dried overmagnesium sulphate and concentrated by evaporation. The residue ischromatographed on silica gel with the use of benzene and benzene/ethylacetate mixtures as eluant. The fractions containing the desired nitrile[R_(f) = 0.5 in the eluant system benzene/chloroform/ethyl acetate(4:4:2)] are combined and concentrated by evaporation. The residue iscrystallised from ethyl acetate/petroleum ether to obtain6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.

EXAMPLE 5

1.1 g (0.0225 mole) of sodium cyanide is added at 0°-5° with stirring to60 ml of isopropanol saturated with ammonia. After 5 minutes, a solutionof 1.61 g (0.0045 mole) of6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehydein ca. 20 ml of isopropanol is added together with 3.9 g of manganesedioxide. After a further 10 minutes, an addition is made of 3.5 g ofmanganese dioxide (total 0.09 mole), and the mixture stirred for 4 hoursat 0°-5°. After the addition of 50 ml of methylene chloride, thereaction mixture is filtered, and the filtrate concentrated byevaporation. The residue is dissolved in a little ethanol, and thissolution chromatographed through ca. 80 g of silica gel (Merck, 0.063 -0.2 mm particle size) with the use of the system ethyl acetate/ethanol(10:1) as the eluant, collecting fractions each of ca. 20 ml.

The fractions 13-16 are combined, concentrated by evaporation, and theresidue recrystallised from ethyl acetate/petroleum ether to obtain6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxylicacid isopropyl ester, M.P. 229°-230°.

The fractions 21-25 are likewise combined and then concentrated byevaporation; the residue is subsequently recrystallised from ethylacetate/petroleum ether to obtain6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 226°-228°.

The starting material is prepared as follows:

a. A suspension of 1.3 g of6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-methanoland 3.4 g of manganese dioxide in 200 ml of benzene is refluxed for 2hours. The reaction mixture is then filtered and the filtrateconcentrated by evaporation. The resulting foam is dissolved in a littleethyl acetate and the solution chromatographed on ca. 60 g of silica gel(Merck, 0.063 - 0.2 mm particle size) with ethyl acetate as the eluant.Fractions each of ca. 80 ml are collected. The fractions 4-8 arecombined, concentrated by evaporation, and the residue crystallised froman ethyl acetate/ether/petroleum ether mixture to obtain6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde, M.P. 182°-189°.

EXAMPLE 6

2 ml of a 20% solution of dimethylamine in dioxane is added to asolution of 0.050 g (0.0083 mole) of6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxylicacid isopropyl ester (obtained according to Example 5) in 2 ml ofmethanol. After 5 hours' standing at 25°, the solution is concentratedby evaporation and the residue dissolved in a little ethyl acetate; theundissolved parts are removed by filtration, and petroleum ether addedto the filtrate. The resulting product after filtration isN,N-dimethyl-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide,M.P. 124°-134°.

What we claim is:
 1. A pharmaceutical preparation useful in thetreatment of states of tension, agitation and epilepsy which comprises adiazepine derivative of the general formula I ##STR8## wherein R₁represents hydrogen, R₂ and R₃ each independently represent hydrogen oralkyl having 1 to 6 carbon atoms, ring A is unsubstituted, orsubstituted in the 8-position by halogen up to atomic number 35, ortrifluoromethyl or nitro, and ring B is unsubstituted, or substituted inone o-position by halogen up to atomic number 35, or by trifluoromethylor a nitro group, or the 5-oxide or a pharmaceutically acceptable acidaddition salt of a compound of the formula I, together with an inertpharmaceutical carrier.
 2. A pharmaceutical preparation as claimed inclaim 1, containing a compound of the formula I given in claim 1, inwhich formula R₁ represents hydrogen, R₂ and R₃ each independentlyrepresent hydrogen or alkyl having 1 to 6 carbon atoms, ring A issubstituted in the 8-position by chlorine, ring B is unsubstituted, orsubstituted in the o-position by fluorine or chlorine, together with aninert pharmaceutical carrier.
 3. A pharmaceutical preparation as claimedin claim 1, containing a compound of the formula I given in claim 1, inwhich formula R₁ represents hydrogen, R₂ and R₃ each independentlyrepresent hydrogen or methyl or ethyl, ring A is substituted in the8-position by chlorine, and ring B is unsubstituted, or substituted inthe o-position by fluorine or chlorine, together with an inertpharmaceutical carrier.
 4. A method for the treatment of states oftension and agitation characterized by oral, rectal or parenteraladministration of a therapeutically effective amount of a diazepinederivative of the general formula I ##STR9## wherein R₁ representshydrogen, R₂ and R₃ each independently represent hydrogen or alkylhaving 1 to 6 carbon atoms, ring A is unsubstituted, or substituted inthe 8-position by halogen up to atomic number 35, or trifluoromethyl ornitro, and ring B is unsubstituted, or substituted in one o-position byhalogen up to atomic number 35, or by trifluoromethyl or a nitro group,or of the 5-oxide or of an addition salt of a compound of the generalformula I with a pharmaceutically acceptable inorganic or organic acid.